Benzoylurea compounds, and pesticidal and pharmaceutical compositions comprising same

ABSTRACT

The invention relates to new benzoylurea compounds of the general formula  &lt;IMAGE&gt;  wherein R1 is a halogen atom, R2 is a hydrogen atom or a halogen atom, R3 is a hydrogen atom or represents 1 or 2 substituents which are selected from the group consisting of chlorine, methyl and trifluoromethyl, R4 is a hydrogen atom, an alkyl group having 1-6 carbon atoms or a cycloalkyl group having 3-6 carbon atoms, R5 is a hydrogen atom or an alkyl group having 1-4 carbon atoms, and A is a phenyl group or a heteroaryl group having 1 or 2 nitrogen atoms, which groups may be substituted with 1-3 substituents which are selected from the group consisting of halogen, and alkyl, alkoxy, haloalkyl and haloalkoxy having 1-4 carbon atoms. The compounds have an insecticidal and acaricidal activity. After having been processed to compositions, the compounds may be used for control of insects and/or mites in a dosage from 1 to 5000 g of active substance per hectare. In addition the compounds have an anti-tumor activity and may be used in pharmaceutical compositions.

The invention relates to new benzoylurea compounds and to a method ofpreparing these compounds. The invention also relates to compositionswith insecticidal and acaricidal activity which comprise these compoundsand to the use of these compositions for controlling insects and/ormites. The invention further relates to pharmaceutical compositionscomprising same compounds and to the use of these compositions forcombating tumors.

N-Benzoyl-N'-phenylurea compounds having insecticidal activity are knownfrom Applicants' Netherlands patent application No. 7105350. In Chem.Abstracts 91, 20141 (1979) benzoylurea compounds are described havingboth an insecticidal and an acaricidal activity, for exampleN-(2,6-difluorobenzoyl)-N'-(4-benzyloxyphenyl)urea. This compound,however, proves to have no marked acaricidal activity in practicallyacceptable dosages.

It has surprisingly been found that benzoylurea compounds of the generalformula ##STR2## wherein R₁ is a halogen atom,

R₂ is a hydrogen atom or a halogen atom,

R₃ is a hydrogen atom or represents 1 or 2 substitutents which areselected from the group consisting of chlorine, methyl ortrifluoromethyl,

R₄ is a hydrogen atom, an alkyl group having 1-6 carbon atoms or acycloalkyl group having 3-6 carbon atoms,

R₅ is a hydrogen atom or an alkyl group having 1-4 carbon atoms,

A is a phenyl group or a heteroaryl group having 1 or 2 nitrogen atoms,which groups may be substituted with 1-3 substituents which are selectedfrom the group consisting of halogen, and alkyl, alkoxy, haloalkyl andhaloalkoxy having 1-4 carbon atoms, and

X is an oxygen or sulphur atom,

not only have strong insecticidal properties, but also show aninteresting acaricidal activity.

Of the above compounds especially those compounds prove to have a highacaricidal activity, which correspond to the general formula ##STR3##wherein R₁ ' and R₂ ' are both fluorine atoms, or wherein R₁ ' is achlorine atom and R₂ ' is a hydrogen atom,

R₄ ' is a n-propyl, isopropyl, or cyclopropyl group, and

R₆ is a hydrogen atom or represents 1-2 substituents which are selectedfrom the group consisting of halogen, and alkyl, alkoxy, haloalkyl andhaloalkoxy having 1-4 carbon atoms.

Of these last-mentioned compoundsN-(2,6-difluorobenzoyl)-N'-[4-(α-cyclopropyl-4-chlorobenzylideneaminooxymethyl)phenyl]urea(1) proves to be eminently suitable to be applied in controlling insectsand mites.

Other examples of new benzoylurea compounds having insecticidal andacaricidal activity, according to the invention are:

(2)N-(2,6-difluorobenzoyl)-N'-[4-(1-phenylpropylideneaminooxymethyl)phenyl]urea,

(3)N-(2-chlorobenzoyl)-N'-[4-(1-phenylbutylideneaminooxymethyl)phenyl]urea,

(4)N-(2,6-difluorobenzoyl)-N'-[4-(1-phenylbutylideneaminooxymethyl)phenyl]urea,

(5)N-(2-chlorobenzoyl)-N'-[4-(1-phenyl-2-methylpropylideneaminooxymethyl)phenyl]urea,

(6)N-(2,6-difluorobenzoyl)-N'-[4-{1-(4-chlorophenyl)propylideneaminooxymethyl}phenyl]urea,

(7)N-(2-chlorobenzoyl)-N'-[4-{1-(4-chlorophenyl)butylideneaminooxymethyl}phenyl]urea,

(8)N-(2,6-difluorobenzoyl)-N'-[4-{1-(4-chlorophenyl)butylideneaminooxymethyl}phenyl]urea,

(9)N-(2-chlorobenzoyl)-N'-[4-{1-(4-chlorophenyl)-2-methylpropylideneaminooxymethyl}phenyl]urea,

(10)N-(2,6-difluorobenzoyl)-N'-[4-{1-(4-chlorophenyl)-2-methylpropylideneaminooxymethyl}phenyl]urea,

(11)N-(2-chlorobenzoyl)-N'-[4-{1-(2,4-dichlorophenyl)pentylideneaminooxymethyl}phenyl]urea,

(12)N-(2,6-difluorobenzoyl)-N'-[4-{1-(2,4-dichlorophenyl)pentylideneaminooxymethyl}phenyl]urea,

(13)N-(2-chlorobenzoyl)-N'-[4-{1-(3,4-dichlorophenyl)butylideneaminooxymethyl}phenyl]urea,

(14)N-(2,6-difluorobenzoyl)-N'-[4-{1-(3,4-dichlorophenyl)butylideneaminooxymethyl}phenyl]urea,

(15)N-(2-chlorobenzoyl)-N'-[4-{1-(pyridyl-2)butylideneaminooxymethyl}phenyl]urea,

(16)N-(2,6-difluorobenzoyl)-N'-[4-{1-(pyridyl-2)butylideneaminooxymethyl}phenyl]urea,

(17)N-(2-chlorobenzoyl)-N'-[4-(α-cyclopropyl-4-chlorobenzylideneaminooxymethyl)phenyl]urea,

(18)N-(2,6-difluorobenzoyl)-N'-[4-{1-(4-chlorophenyl)ethylideneaminooxymethyl}phenyl]urea,

(19)N-(2-chlorobenzoyl)-N'-[4-(1-phenylpropylideneaminooxymethyl)phenyl]urea,

(20) N-(2,6-difluorobenzoyl)-N'-(4-benzylideneaminooxymethylphenyl)urea,

(21)N-(2,6-difluorobenzoyl)-N'-[4-{1-(4-methylphenyl)pentylideneaminooxymethyl}phenyl]urea,

(22)N-(2-chlorobenzoyl)-N'-[4-{1-(2,4-dichlorophenyl)butylideneaminooxymethyl}phenyl]urea,

(23)N-(2,6-difluorobenzoyl)-N'-[4-{1-(2,4-dichlorophenyl)butylideneaminooxymethyl}phenyl]urea,

(24)N-(2,6-difluorobenzoyl)-N'-[4-{1-(3,4-dichlorophenyl)butylideneaminooxymethyl}phenyl]thiourea,

(25)N-(2-chlorobenzoyl)-N'-[3-chloro-4-{1-(2,4-dichlorophenyl)butylideneaminooxymethyl}phenyl]urea,

(26)N-(2,6-difluorobenzoyl)-N'-[3-chloro-4-{1-(2,4-dichlorophenyl)butylideneaminooxymethyl}phenyl]urea,

(27)N-(2-chlorobenzoyl)-N'-[4-1-{1-(4-methoxyphenyl)butylideneaminooxymethyl}phenyl]urea,

(28)N-(2-chlorobenzoyl)-N'-[3-chloro-4-(1-phenylbutylideneaminooxymethyl)phenyl]urea,

(29)N-(2,6-difluorobenzoyl)-N'-[3-chloro-4-(1-phenylbutylideneaminooxymethyl)phenyl]urea,

(30)N-(2-chlorobenzoyl)-N'-[4-{1-(4-methylphenyl)phentylideneaminooxymethyl}phenyl]urea,

(31)N-(2,6-difluorobenzoyl)-N'-[4-{1-(4-trifluoromethylphenyl)-2-methylpropylideneaminooxymethyl}phenyl]urea,

(32)N-(2,6-difluorobenzoyl)-N'-[4-{1-(4-bromophenyl)-2-methylpropylideneaminooxymethyl}phenyl]urea,

(33)N-(2-chlorobenzoyl)-N'-[4-{1-(1-phenylbutylideneaminooxy)ethyl}-phenyl]urea,

(34)N-(2,6-difluorobenzoyl)-N'-[4-{1-(1-phenylbutylideneaminooxy)ethyl}-phenyl]urea,

(35)N-(2,6-difluorobenzoyl)-N'-[4-(1-phenyl-2-methylpropylideneaminooxymethyl)phenyl]urea,and

(36)N-(2-chlorobenzoyl)-N'-[4-{1-(4-chlorophenyl)propylideneaminooxymethyl}phenyl]urea.

The new benzoylurea compounds of the invention can occur in twostereoisomers, viz. the syn- and the anti-form, while, of course, alsomixtures of these stereoisomers are possible in all ratios. If desired,these stereoisomers can be separated from each other by using technicswhich are known for this purpose, such as recrystallization and/orcolumn chromatography. The activity may be influenced by the stericalconfiguration.

The substances according to the invention may be used for the control ofmites and insects in agriculture and horticulture, in forests and insurface water, as well as for the protection of textile against attackby, for example in stored cereals, and against mites and insects in theveterinary and medical-hygienic sector.

The substances according to the invention can also be used for thecontrol of insects living in the manure of warm-blooded animals, such ascows, pigs and hens. For this application, the active compounds can beadministered orally to the animals, for example, mixed through the food,so that they land in the manure after some time ("through-feeding").

The compounds according to the invention are particularly active againstlarvae and eggs of mites and insects. In principle, the compounds may beused against all insects mentioned in Pestic. Sci. 9, 373-386 (1978).

In addition it has been found, that the compounds of the invention havecytostatic or anti-tumor activity, in that they show an inhibitingeffect on the growth of tumors. For use in pharmaceutical compositionsfor combating tumors in living beings the compounds of the inventionshould be incorporated into pharmaceutically acceptable carriers.

For practical pesticidal application the substances in accordance withthe invention are usually processed to compositions. In suchcompositions the active substance is mixed with solid carrier materialor dissolved or dispersed in liquid carrier material, if desired incombination with auxiliary substances, for example, emulsifiers, wettingagents, dispersible agents and stabilizers.

Examples of compositions according to the invention are aqueoussolutions and dispersions, oily solutions and oily dispersions,solutions in organic solvents, pastes, dusting powders, dispersiblepowders, miscible oils, granules, pellets, invert emulsions, aerosolcompositions and fumigating candles.

Dispersible powders, pastes and miscible oils are compositions inconcentrate from which are diluted prior to or during use.

The invert emulsions and solutions in organic solvents are mainly usedin air application; namely when large areas are treated with acomparatively small quantity of composition. The invert emulsion can beprepared shortly before or even during spraying in the sprayingapparatus by emulsifying water in an oily solution or an oily dispersionof the active substance. The solutions of the active substance inorganic solvents may be provided with a phytotoxicity-reducingsubstance, for example, wool fat, wool fatty acid or wool fatty alcohol.

A few forms of composition will be described in greater detailhereinafter by way of example.

Granular compositions are prepared by taking up, for example, the activesubstance in a solvent or dispersing it in a diluent and impregnatingthe resulting solution/suspension, if desired in the presence of abinder, on granular carrier material, for example porous granules (forexample pumice and attaclay), mineral non-porous granules (sand orground marl), organic granules (for example, dried coffee grounds, cuttobacco stems and ground corncobs). A granular composition can also beprepared by compressing the active substance together with powderedminerals in the presence of lubricants and binders and disintegratingthe compressed product to the desired grain size and sieving it.Granular compositions can be prepared in a different manner by mixingthe active substance in powder form with powdered fillers, andglomulating the mixture then with liquid to the desired particle size.

Dusting powders can be obtained by intimately mixing the activesubstance with an inert solid powdered carrier material, for example,talcum.

Dispersible powders are prepared by mixing 10 to 80 parts by weight of asolid inert carrier, for example kaolin, dolomite, gypsum, chalk,bentonite, attapulgite, colloidal SiO₂ or mixtures of these and similarsubstances, with 10 to 80 parts by weight of the active substance, 1 to5 parts by weight of a dispersing agent, for example the ligninesulphonates or alkylnaphthalene sulphonates known for this purpose,preferably also 0.5 to 5 parts by weight of a wetting agent, forexample, fatty alcohol sulphates, alkyl aryl sulphonates, fatty acidcondensation products, or polyoxyethylene compounds, and finally, ifdesired, other additives.

For the preparation of miscible oils the active compound is dissolved ina suitable solvent which preferably is poorly water-miscible, and one ormore emulsifiers are added to this solution. Suitable solvents are, forexample, xylene, toluene, petroleum distillates which are rich inaromates, for example, solvent naphtha, distilled tar oil and mixturesof these liquids. As emulsifiers may be used, for example,polyoxyethylene compounds and/or alkyl aryl sulphonates. Theconcentration of the active compound in these miscible oils is notrestricted to narrow limits and may vary, for example, between 2 and 50%by weight. In addition to a miscible oil may also be mentioned as aliquid and highly concentrated primary composition a solution of theactive substance in a readily water-miscible liquid, for example, aglycol, or glycol ether, to which solution a dispersion agent and, ifdesired, a surface-active substance has been added. When diluting withwater shortly before or during spraying, an aqueous dispersion of theactive substance is then obtained.

An aerosol composition according to the invention is obtained in theusual manner by incorporating the active substance, if desired in asolvent, in a volatile liquid to be used as a propellant, for example, amixture of chlorine-fluorine derivatives of methane and ethane, amixture of lower hydrocarbons, dimethyl ether, or gases such as carbondioxide, nitrogen and nitrous oxide.

Fumigating candles or fumigating powders, i.e. compositions which, whileburning, can generate a pesticidal smoke, are obtained by taking up theactive substance in a combustible mixture which may contain as a fuel asugar or a wood, preferably in a ground form, a substance to maintaincombustion, for example, ammonium nitrate or potassium chlorate, andfurthermore a substance to delay combustion, for example, kaolin,bentonite and/or colloidal silicic acid.

In addition to the above-mentioned ingredients, the agents according tothe invention may also contain other substances known for use in thistype of agents. For example, a lubricant, e.g., calcium stearate ormagnesium stearate, may be added to a dispersible powder or a mixture tobe granulated. "Adhesives", for example, polyvinylalcohol cellulosederivatives or other colloidal materials, such as casein, may also beadded so as to improve the adhesion of the presticide to the crop.Furthermore, a substance may be added to reduce the phytotoxicity of theactive substance, carrier material or auxiliary substance, for example,wool fat or wool fatty alcohol.

Pesticidal compounds known per se may also be incorporated in thecompositions according to the invention. As a result of this theactivity spectrum of the composition is widened and synergism may occur.

For use in such a combination composition are to be considered thefollowing known insecticidal, acaricidal and fungicidal compounds.

Insecticides, for example:

1. organic chlorine compounds, for example6,7,8,9,10,10-hexachloro-1,5,5a,6,9,9a-hexahydro-6,9-methano-2,4,3-benzo[e]-dioxathiepine-3-oxide;

2. carbamates, for example, 2-dimethylamino-5,6-dimethylpyrimidin-4-yldimethyl carbamate and 2-isopropoxyphenyl methylcarbamate;

3. di(m)ethylphosphates, for example,2-chloro-2-diethylcarbamoyl-1-methylvinyl-,2-methoxycarbonyl-1-methylvinyl-, 2-chloro-1-(2,4-dichlorophenyl)vinyl-,and 2-chloro-1-(2,4,5-trichlorophenyl)vinyl di(m)ethyl phosphate;

4. 0,0-di(m)ethyl phosphorothioates, for example,0(S)-2-methylthioethyl-, S-2-ethylsulphinylethyl-,S-2-(1-methylcarbamoylethylthio)ethyl-, 0-4-bromo-2,5-dichlorophenyl-,0-3,5,6-trichloro-2-pyridyl-, 0-2-isopropyl-6-methylpyrimidin-4-yl-, and0-4-nitrophenyl 0,0-di(m)ethyl phosphorothioate;

5. 0,0-di(m)ethyl phosphorodithioates, for example,S-methylcarbamoylmethyl-, S-2-ethylthioethyl-,S-(3,4-dihydro-4-oxobenzo[d]-1,2,3-triazin-3-ylmethyl)-,S-1,2-di(ethoxycarbonyl)ethyl-,S-6-chloro-2-oxobenzoxazolin-3-ylmethyl-, andS-2,3-dihydro-5-methoxy-2-oxo-1,3,4-thiadiazol-3-ylmethyl0,0-di(m)ethylphosphorodithioate;

6. phosphonates, for example, dimethyl2,2,2-trichloro-1-hydroxyethylphosphonate;

7. natural and synthetic pyrethroids;

8. amidines, for example,N'-(2-methyl-4-chlorophenyl)-N,N-dimethylformamidine;

9. microbial insecticides, such as Bacillus thuringiensis;

10. carbamoyl-oximes, such as S-methyl N-(methylcarbamoyloxy)thioacetamidate; and

11. other benzoylurea compounds, such asN-(2,6-difluorobenzoyl)-N'-(4-chlorophenyl)urea.

Acaricides, for example:

1. organic tin compounds, for example, tricyclohexyl tin hydroxide anddi[tri-(2-methyl-2-phenylpropyl)tin]oxide;

2. organic halogen compounds, for example isopropyl4,4'-dibromobenzilate, 2,2,2-trichloro-1,1-di(4-chlorophenyl)ethanol and2,4,5,4'-tetrachlorodiphenyl sulphone;

3. synthetic pyrethroids, and furthermore:3-chloro-α-ethoxyimino-2,6-dimethoxybenzyl benzoate and 0,0-dimethylS-methylcarbamoyl methyl phosphorothioate.

Fungicides, for example:

1. organic tin compounds, for example, triphenyl tin hydroxide andtriphenyl tin acetate;

2. alkylene bisdithiocarbamates, for example, zincethylenebisdithiocarbamate and maganese ethylene bisdithiocarbamate;

3. 1-acyl- or 1-carbamoyl-N-benzimidazole (-2) carbamates and 1,2-bis(3-alkoxycarbonyl-2-thiureido)benzene, and furthermore2,4-dinitro-6-(2-octylphenylcrotonate), 1-[bis(dimethylamino)phosphoryl]-3-phenyl-5-amino-1,2,4-triazole,N-trichloromethylthiophthalimide,N-trichloromethylthiotetrahydrophthalimide,N-(1,1,2,2-tetrachloroethylthio)-tetrahydrophthalimide,N-dichlorofluoromethylthio-N-phenyl-N,N'-dimethylsulphamide,tetrachloroisophthalonitrile, 2-(4'-thiazolyl)-benzimidazole,5-butyl-2-ethylamino-6-methylpyrimidine-4-yl-dimethylsulphamate,1-(4-chlorophenoxy)-3,3-dimethyl-1(1,2,4-triazole-1-yl)-2-butanone,α-(2-chlorophenyl)-α-(4-chlorophenyl)-5-pyrimidinemethanol,1-(isopropylcarbamoyl)-3-(3,5-dichlorophenyl)hydantoin,N-(1,1,2,2-tetrachloroethylthio)-4-cyclohexene-1,2-carboximidine,N-trichloromethylmercapto-4-cyclohexene-1,2-dicarboximidine,N-tridecyl-2,6-dimethylmorpholine.

The dosages of the pesticidal composition according to the inventiondesired for practical application will, of course, depend on variousfactors, for example, application area, selected active substance, formor composition, nature and extent of the infection, and the weaterconditions.

In general it holds that favourable results are achieved with a dosagecorresponding to 1 to 5000 g of the active substance per hectare. Forthe above-described "through-feeding" the active substance is mixedthrough the food in a quantity which is effective for insecticidalapplication.

The compounds according to the invention are new substances which can beprepared in a manner known per se for related compounds.

For example, the compounds according to the invention can be prepared byreacting a substituted aniline of the general formula ##STR4## whereinR₃, R₄, R₅ and A have the above-mentioned meanings, with a compound ofthe general formula ##STR5## wherein R₁, R₂ and X also have theabove-mentioned meanings.

The new compounds according to the invention can also be prepared byreacting a substituted benzamide of the general formula ##STR6## whereinR₁ and R₂ have the above-mentioned meanings, with a compound of thegeneral formula ##STR7## wherein R₃, R₄, R₅, X and A also have theabove-mentioned meanings.

The above reactions are preferably carried out in the presence of anorganic solvent, such as an aromatic hydrocarbon, an alkyl halide, acyclic or not cyclic dialkyl ether, or acetonitril, at a reactiontemperature between 0° C. and the boiling point of the solvent used.

Although the above-indicated methods of preparing are the best suitable,the new compounds can also be prepared in a different manner, forexample, as described in the above-mentioned Netherlands patentapplication No. 7105350 or according to the methods described in theNetherlands patent application Nos. 7806678 or 8005588.

The invention will now be described in more detail with reference to thefollowing specific examples.

EXAMPLE I

Preparation ofN-(2,6-difluorobenzoyl)-N'-[4-(α-cyclopropyl-4-chlorobenzylideneaminooxymethyl)phenyl]urea(1).

36.6 g of 2,6-difluorobenzoylisocyanate in 50 ml of dry diethyl etherwere added to a solution of 59.0 g4-(α-cyclopropyl-4-chlorobenzylideneaminooxymethyl)aniline in 700 ml ofdry diethylether with external cooling at 0°-10° C. After stirring for 3hours at 0°-10° C. the formed precipitate was sucked off, washed withdiethyl ether, and dried. The product obtained in a yield of 76.0 g waschromatographed over silica, chloroform being used as an eluent. Thedesired product was isolated in a yield of 60,7 g having a purity of atleast 95% (PMR). The product obtained had a melting range of 145°-175°C. and comprised the syn- and anti-form in approximately equal amounts.In another experiment the desired product was obtained as a mixture ofthe syn- and anti-form in a ratio of 85:15; melting point 187°-191° C.

The starting aniline was obtained from the corresponding nitro compoundby reduction with hydrogen under the influence of Raney nickel as acatalyst; a mixture of ethyl acetate and ethanol in a ratio of 2:1 byvolume was used as a solvent.1-Nitro-4-(α-cyclopropyl-4-chlorobenzylideneaminooxymethyl)benzene wasprepared by a reaction of (4-chlorophenyl)-cyclopropylketoneoxime with4-nitrobenzylbromide in methanol as a solvent in the presence of sodiummethoxide. The reaction can also be carried out under the influence ofsodiumhydride as a base in dimethylformamide as a solvent. The oximeused was obtained from the corresponding ketone by a reaction withhydroxylamine. HCl in a mixture of water and ethanol and under theinfluence of NaOH.

In a corresponding manner, in which, if desired, instead of diethylether acetonitrile was used as a solvent for the urea-formation, thefollowing compounds were prepared;

The compound numbers correspond with the numbers given before in thespecification:

    ______________________________________                                        compound no.                                                                             melting point                                                                             remarks                                                ______________________________________                                         2         120-122° C.                                                  3         106,5-108,5° C.                                              4         144,5-146,5° C.                                              5         114-117° C.                                                                        mixture syn-anti                                        6         144-159° C.                                                  7         141-143° C.                                                  8           141-144,5° C.                                              9         154,5-157,5° C.                                             10         203-208° C.                                                 11         113-116° C.                                                                        anti-form                                              12         124-132° C.                                                                        syn- or anti-form                                      13         153-155° C.                                                                        syn- or anti-form                                      14         128-130° C.                                                                        syn- or anti-form                                      15         139,5-141,5° C.                                             16         128-130° C.                                                 17         182-187° C.                                                                        mixture syn-anti                                       18         176-180° C.                                                 19         112-114° C.                                                 20         150-152° C.                                                 21         158-160° C.                                                 22         109-112° C.                                                 23         142-147° C.                                                 24         viscous liquid*                                                                           23% anti-, 67% syn-form                                25         133-146° C.                                                 26         125-135° C.                                                 27         164-167° C.                                                 28         162-164° C.                                                 29         158-161° C.                                                 30         130-135° C.                                                 31         130-138° C.                                                 32         207-210° C.                                                 33         107° C.                                                     34         117°  C.                                                    35         137° C.                                                     36         153-161° C.                                                 ______________________________________                                         *note:                                                                        compound no. 24: PMR (CDCl.sub.3) syn: δ (NH) 12, 22: 9, 20: anti:      δ (NH) 12, 28; 9, 15.                                              

In case this has been determined, it has been stated in the above surveywhether the substance obtained is one of the both stereoisomers or amixture of both. A considerable melting range generally points to amixture of stereoisomers.

The above compounds could also be obtained easily by starting fromsubstituted benzamides and substituted benzylideneaminooxymethylphenylisocyanates; same reaction conditions as above. The starting phenylisocyanates were prepared from the corresponding anilines by a reactionwith phosgene in an inert organic solvent, e.g. an aromatic solvent liketoluene; reaction temperature between 0° C. and the boiling point of thesolvent. So compound no (1) could be prepared from 2,6-difluorobenzamideand 4-(α-cyclopropyl-4-chlorobenzylideneaminooxymethyl)phenyl isocyanatein dry diethylether at 0°-10° C. in a yield of approximately 70%.

EXAMPLE II

(a) Preparation of a solution of an active substance, viz.N-(2,6-difluorobenzoyl)-N'-[4-(α-cyclopropyl-4-chlorobenzylidene-aminooxymethyl)phenyl]urea,in a water-miscible liquid ("liquid")

10 g of the above active substance were dissolved in a mixture of 10 mlof isophorone and approximately 70 ml of dimethylformamide, after whichpolyoxyethylene glycol ricinyl ether was added as an emulsifier in aquantity of 10 g.

In a corresponding manner the other active substances were processed to10 or 20% "liquids".

In a corresponding manner "liquids" were obtained inN-methylpyrrolidone, dimethylformamide, and a mixture ofN-methylpyrrolidone and isophorone as solvents.

(b) Preparation of a solution of the active substance in an organicsolvent.

200 mg of the active substance to be tested were dissolved in 1,000 mlof acetone in the presence of 1.6 g of nonylphenolpolyoxyethylene. Afterpouring out into water this solution can be used as a spray liquid.

(c) Preparation of an emulsifiable concentrate of the active substance.

10 g of the active substance to be tested were dissolved in a mixture of15 ml of isophorone and 70 ml of xylene; to this solution were added 5 gof a mixture of a polyoxyethylene sorbitan ester and an alkyl benzenesulphonate as an emulsifier.

(d) Preparation of a dispersible powder (WP) of the active substance.

25 g of the active substance to be tested were mixed with 68 g of kaolinin the presence of 2 g of sodium butylnaphthalene sulphonate and 5 g oflignine sulphonate.

(e) Preparation of a suspension concentrate (flowable) of the activesubstance.

A mixture of 10 g of the active substance, 2 g of lignine sulphonate and0.8 g of a sodium alkylsulphate were supplied with water till a totalamount of 100 ml.

(f) Preparation of a granule of the active substance.

7.5 g of the active substance, 5 g of sulphite lye and 87.5 g of grounddolomite were mixed, after which the resulting mixture was processed toa granular composition by means of the so-called compacting method.

EXAMPLE III

Young Brussels sprouts plants, approximately 15 cm high, were sprayedwith compositions obtained according to Example II (b) in variousconcentrations; in addition approximately 250 mg of an alkylatedphenolpolyoxyethelene compound (Citowett) per liter had been added tothese compositions. After the plants had dried up, they were placed inplexiglass cylinders and then infected with 5 larvae of Pieris brassicae(caterpillars of the cabbage white butterfly) in the third larval stage(L3). The cylinders were then covered with a gauze and stored, analternating light-dark cycle of 16 hours light and 8 hours dark beingused; temperature in the light 24° C., relative humidity (RH) 70%,temperature in the dark 19° C., 80-90% RH. After 5 days the mortalitypercentage of the larvae was established. Each experiment has beencarried out in triplicate. The average results of the experiments arerecorded in table A below. The meanings of the symbols indicated in thetable are as follows:

+=90-100% mortality

±=50-90% mortality

-=<50% mortality

                  TABLE A                                                         ______________________________________                                        Insecticidal activity against larvae (L3) of Pieris brassicae                         concentration in mg of active ingredient per liter                    Compound no.                                                                            300    100    30   10  3   1    0,3 0,1 0,03                        ______________________________________                                         1        +      +      +    +   +   +    +   ±                                                                              -                           17        +      +      +    +   +   +    -                                   18        +      +      +    +   +   +    +   ±                                                                              -                           19        +      +      +    +   +   +    -                                   20        +      +      +    +   +   +    +   +   -                            3        +      +      +    +   +   +    -                                    4        +      +      +    +   +   +    ±                                                                              -                                5        +      +      +    +   +   +    +   -                                6        +      +      +    +   +   +    +   ±                                                                              -                            7        +      +      +    +   +   +    +   -                                8        +      +      +    +   +   +    +   +   -                           10        +      +      +    +   +   +    +   +   -                           11        +      +      +    +   +   +    -                                   12        +      +      +    +   +   +    +   ±                                                                              -                           14        +      +      +    +   +   +    ±                                                                              -                               15        +      +      +    +   +   +    -                                   16        +      +      +    +   +   +    ±                                21        +      +      +    +   +   +    -                                   22        +      +      +    +   +   +    +   -                               23        +      +      +    +   +   +    +   +   -                           24        +      +      +    +   +   +    ±                                                                              -                               25        +      +      +    +   +   +    -                                   26        +      +      +    +   +   +    -                                   27        +      +      +    +   +   +    -                                   29        +      +      +    +   +   +    -                                   30        +      +      +    +   +   +    -                                   33        +      +      +    +   +   +    -                                   34        +      +      +    +   +   +    +   ±                                                                              -                           35        +      +      +    +   +   +    ±                                                                              -                               36        +      +      +    +   +   +    -                                   ______________________________________                                    

In practice insecticidal and acaricidal compositions are used inquantities of approximately 100 liters per hectare. The coverage of theplants with the composition, however, is considerably less in practicethan in a laboratory or greenhouse experiment as described above.Accordingly, it has proven that in practice the dosage should beimproved with a factor of 10 to achieve the same efficiency. Thereforein practical application the above quantities with insecticidal activitycorrespond with approximately 1 to 3000 grams of active substance perhectare.

EXAMPLE IV

Young potato plants, approximately 15 cm high, were sprayed with thecompositions obtained according to Example II (b) in variousconcentrations; in addition approximately 250 mg of Citowett per literhad been added to these compositions. After the plants had dried-up,plexiglass cylinders were placed over the plants. The plants were theninfected with 10 larvae of Leptinotarsa decemlineata (larvae of theColorado beetle) in the third larval stage (L3). The infected plantswere stored as indicated in Example III. After 5 days the mortalitypercentage of the larvae was established. The experiments have beencarried out in triplicate. The average results of the experiments arerecorded in table B below. The meanings of the symbols are the same asin Example III.

                  TABLE B                                                         ______________________________________                                        Insecticidal activity against larvae of Leptinotarsa decemlineata                     concentration in mg of active ingredient per liter                    Compound no.                                                                            300     100     30   10   3    1    0,3                             ______________________________________                                         1        +       +       +    +    +    ± -                               23        +       +       +    +    +    ± -                               ______________________________________                                    

In practice the above quantities with insecticidal activity correspondwith approximately 10 to approximately 3000 grams of active substanceper hectare.

EXAMPLE V

The growth tips of broad bean plants having four well developed leaveswere removed, after which the plants were sprayed until dripping withcompositions obtained according to Example II (b) in variousconcentrations; in addition approximately 250 mg of Citowett per literhad been added to these compositions. After the plants had dried-up,they were placed in perspex cylinders and then infected with 5 larvae ofSpodoptera littoralis (Egyptian cotton caterpillar) in the third larvalstage (L3). The cylinders were then covered with a gauze and then storedas indicated in Example III. After 5 days the mortality percentage ofthe larvae was established. Each experiment was carried out intriplicate. The average results of the experiments are recorded in TableC. The meanings of the symbols are the same as in Example III.

                  TABLE C                                                         ______________________________________                                        Insecticidal activity against larvae (L3) of Spodoptera littoralis                    concentration in mg of active ingredient per liter                    Compound no.                                                                            300     100     30   10   3    1    0,3                             ______________________________________                                         1        +       +       +    +    +    +    -                               17        +       +       +    +    ± -                                    19        +       +       ± ± -                                          3        +       +       +    +    -                                          4        +       +       +    +    ± -                                     5        +       +       +    +    -                                          6        +       +       +    +    ± -                                     7        +       +       +    +    +    -                                     8        +       +       +    +    +    ± -                                9        +       +       +    +    +    -                                    14        +       +       +    +    ± -                                    22        +       +       +    +    -                                         23        +       +       +    +    -                                         24        +       +       +    ± -                                         28        +       +       +    +    +    -                                    29        +       +       +    +    +    -                                    30        +       +       +    +    +    ± -                               33        +       +       +    +    ± -                                    34        +       +       +    +    ± -                                    35        +       +       +    ± ± ± -                               36        +       +       +    +    ± -                                    ______________________________________                                    

In practice the above quantities with insecticidal activity correspondwith approximately 3 to approximately 1000 grams of active substance perhectare.

EXAMPLE VI

Dwarf French bean plants (Phaseolus vulgaris) having two well developedleaves were infected with Tetranychus cinnabarinus (carnation spidermite) by placing a fixed number of adult female mites on the plants. Twodays after the infection the plants with the adult mites present thereonwere sprayed until dripping with compositions obtained according toExample II (b) in various concentrations; in addition approximately 150mg of an alkylated phenolpolyoxyethylene compound (Citowett) per literhad been added. Five days after the spraying the adult mites wereremoved from the plants. The plants were stored during two weeks in aroom with controlled temperature (T) and humidity (RH), an alternatinglight-dark cycle of 16 hours light and 8 hours dark being used. Light: Tapproximately 24° C., RH approximately 70%; dark: T approximately 19°C., RH 80-90%. Then the reduction of the population, i.e. the mortalityof the number of larvae adults and eggs in comparison with plants whichare not treated with chemicals, was established. The experiments werecarried out in triplicate. The average results of the experiments arerecorded in Table D below. The meanings of the symbols used in the tableare as follows:

+=90-100% reduction of the population; plants free or substantially freefrom spider mites;

±=50-90% reduction of the population;

-=<50% reduction of the population.

N-(2,6-difluorobenzoyl)-N'-(4-benzyloxyphenyl)urea ("known") has beenincluded in the tests by way of comparison.

                  TABLE D                                                         ______________________________________                                        Activity against Tetranychus cinnabarinus (carnation spider mite)                     concentration in mg of active ingredient per liter                    Compund no.                                                                             300     100     30   10   3    1    0,3                             ______________________________________                                        1         +       +       +    +    +    +    -                               2         +       ±    -                                                   3         +       ±    ± -                                              4         +       +       +    ± -                                         5         +       ±    -                                                   6         +       +       ±                                                7         +       ±    -                                                   8         +       +       +    +    +    +    -                               9         +       +       +    +    -                                         10        +       +       ± ±                                           13        +       ±    ± -                                              14        +       +       +    +    ± -                                    16        +                                                                   17        +       +       +    +    -                                         21        +       ±    -                                                   "known"   -                                                                   ______________________________________                                    

In practice the above quantities with acaricidal activity correspondwith approximately 10 to approximately 3000 grams of active substanceper hectare.

Repetitions of the above experiments, wherein the adult mites wereremoved prior to the spraying (Method A), or wherein the spraying wascarried out prior to the infection (Method B), yielded about the sameresults.

EXAMPLE VII

In the same way as described in Example VI, method A, benzoylureacompounds according to the invention were tested on Panonychus ulmi(European red mite). The results are recorded in Table E, wherein thesymbols have the same meanings as in Example VI.

                  TABLE E                                                         ______________________________________                                        Activity against Panonychus ulmi (European red mite)                                  concentration in mg of active ingredient per liter                    Compound no.                                                                            300     100     30   10   3    1    0,3                             ______________________________________                                        1         +       +       +    +    +    ± -                               4         +       +       +    +    -                                         2         +       +       +                                                   3         +       +       +                                                   5         +       +       +                                                   6         +       +       +    +    +    -                                    7         +       +       +    +    ± -                                    8         +       +       +    +    ± -                                    9         +       +       +    +    +    -                                    15        +       +       +                                                   16        +                                                                   17        +       +       +                                                   36        +       +       +    +    +    -                                    ______________________________________                                    

The same results were obtained, when the spraying was carried out priorto the infection (method B).

Liquid compositions are applied on fruit-trees in quantities ofapproximately 1500 liters per hectare. Then the above quantities withacaricidal activity correspond in practice with approximately 150 toapproximately 4500 grams of active substance per hectare.

EXAMPLE VIII

In the same way as indicated in Example VI, method A,N-(2,6-difluorobenzoyl)-N'-[4-(α-cyclopropyl-4-chlorobenzylideneaminooxymethyl)phenyl]urea(1) was tested on Tetranychus urticae (two-spotted spider mite), givingthe results recorded in Table F. Again the meanings of the symbols arethe same as in Example VI.

                  TABLE F                                                         ______________________________________                                        Activity against Tetranychus urticae (two-spotted spider mite)                        concentration in mg of active ingredient per liter                    Compound no.                                                                            300      100     30    10   3     1                                 ______________________________________                                        1         +        +       +     +    +     -                                 ______________________________________                                    

About the same results were obtained, when the experiments were carriedout on a multiresistent strain of Tetranychus urticae.

In practice the above quantities with acaricidal activity correspondwith approximately 30 to approximately 3000 grams of active substanceper hectare.

EXAMPLE IX

Dwarf French bean plants (Phaseolus vulgaris) having two well developedleaves were sprayed from below and from above until dripping with acomposition prepared according to Example II (a); in addition 150 mg ofCitowett per liter had been added to this composition. The compositioncomprisedN-(2,6-difluorobenzoyl)-N'-[4-(α-cyclopropyl-4-chlorobenzylideneaminooxymethyl)phenyl]urea(1) as the active substance in various concentrations. After the plantshad dried-up they were infected with mites of a multiresistent strain ofTetranychus urticae (two-spotted spider mite) in the same way asdescribed in Example VI. The experiments were carried out outdoors.After a fixed number of days (see Table G) the reduction of thepopulation with respect to infected plant material, which was notsprayed with a composition, was estimated. The experiments were carriedout fivefold; the series of experiments were repeated ("rep." in TableG). The average results per test series are recorded in Table G.

                  TABLE G                                                         ______________________________________                                        Acaricidal activity against Tetranychus urticae                                               mortality-%, 1st                                              concentration in mg active                                                                    series, after 16                                                                          mortality-%, rep.;                                ingredient per liter                                                                          days        after 24 days                                     ______________________________________                                        100             100         100                                               30              95          100                                               10              89          100                                               ______________________________________                                    

The quantities indicated in Table G correspond with approximately 10 toapproximately 1000 grams of active substance per hectare under practicalconditions.

EXAMPLE X

Apple trees, headed on 40 cm, were sprayed from below and from aboveuntil dripping with a composition prepared according to Example II (a);in addition 250 mg of an alkylated phenolpolyoxyethylene compound(Neutronix) per liter had been added to this composition. Thecomposition comprised a benzoylurea compound according to the inventionas an active substance. The apple trees were infected previously asdescribed in Example VI with Aculus schlechtendali (apple rust mite),and at the moment of spraying the mites were present in alldevelopment-stages. After 2 and 4 weeks outdoors the reduction of thepopulation of the mites was established. The experiments were carriedout sixfold. The average results are recorded in Table H.

                  TABLE H                                                         ______________________________________                                        Acaricidal activity against Aculus schlechtendali                                                      reduction                                            Compound                                                                              concentration in mg of                                                                         of the population                                    no.     active ingredient per liter                                                                    after 2 wks                                                                             after 4 wks                                ______________________________________                                        1       100              98        97                                                  30              97        95                                         4       100              80        57                                                  30              63        34                                         untreated                                                                             --                0         0                                         ______________________________________                                    

EXAMPLE XI

Inhibition of the growth of tumor cells.

After pre-incubation at 37° C. during 3 hours the compound to be testedwas added in an amount of 5000 ppm to B 16 melanoma cells, growing as amonolayer on a growing medium. The experiment was carried out intriplicate. The mixture was then incubated at 37° C. during 20 hours.After removal of the growing-medium and the test-compound the cells werewashed and fresh growing-medium was added. The amount of cells wasdetermined 48 hours after the beginning of the incubation period with amicrocell Coulter Counter. Compound no. (1) caused 53% inhibition of thecell growth compared to an experiment without a test-compound.

We claim:
 1. Benzoylurea compounds of the general formula ##STR8##wherein R₁ is a halogen atom, R₂ is a hydrogen atom or a halogen atom,R₃is a hydrogen atom or represents 1 or 2 substituents which are selectedfrom the group consisting of chlorine, methyl and trifluoromethyl, R₄ isa hydrogen atom, an alkyl group having 1-6 carbon atoms or a cycloalkylgroup having 3-6 carbon atoms, R₅ is a hydrogen atom or an alkyl grouphaving 1-4 carbon atoms, A is a phenyl group or a heteroaryl grouphaving 1 or 2 nitrogen atoms, which groups may be substituted with 1-3substituents which are selected from the group consisting of halogen,and alkyl, alkoxy, haloalkyl and haloalkoxy having 1-4 carbon atoms andX is an oxygen or sulphur atom.
 2. Benzoylurea compounds as claimed inclaim 1, of the general formula ##STR9## wherein R₁ ' and R₂ ' are bothfluorine atoms, or wherein R₁ ' is a chlorine atom and R₂ ' is ahydrogen atom,R₄ ' is a n-propyl, isopropyl or cyclopropyl group, and R₆is a hydrogen atom or represents 1-2 substituents which are selectedfrom the group consisting of halogen, and alkyl, alkoxy, haloalkyl andhaloalkoxy having 1-4 carbon atoms.
 3. A benzoylurea compound as definedin claim 1, which isN-(2,6-difluorobenzoyl)-N'-[4-(α-cyclopropyl-4-chlorobenzylideneaminooxymethyl)phenyl]urea.4. A benzoylurea compound as defined in claim 1, which isN-(2,6-difluorobenzoyl)-N'-[4,{1-(4-chlorophenyl)butylideneaminooxymethyl}phenyl]urea.5. A benzoylurea compound as defined in claim 1, which isN-(2-chlorobenzoyl)-N'-[4-{1-(4-chlorophenyl)-2-methylpropylideneaminooxymethyl}phenyl]urea.